OBJECTIVE: To study metabolic abnormalities in rheumatoid arthritis, including the hypothesis that hypohistidinemia participates in the pathogenesis of the disease. The approach is based, in part, on three findings: (1) the serum concentration of free histidine (but no other free amino acid) is decreased in patients with rheumatoid arthritis but not in patients with other diseases. (2) L-Histidine (as a histidine-cystine-copper complex), D-penicillamine (as the penicillamine-disulfide-copper complex), and gold thiomalate inhibit (and hyaluronate augments) the heat aggregation of human gamma globulin. (3) Oral L-histidine may be associated with clinical and laboratory improvement in patients with active rheumatoid arthritis. Plans: (1) Study of the chemistry of mechanical grinding-type aggregation of human gamma globulin (e.g., role of the sulfhydryl group and the effect of histidine, penicillamine, and hyaluronate). (2) Further evaluation of oral L-histidine in rheumatoid arthritis particulary regarding effect on anemia and rheumatoid factor. (3) Study of inhibition by histidine of the interaction between cystine, copper and serum protein sulfhydryl groups (a potential explanation for the low serum sulfhydryl concentration of rheumatoid arthritis). (4) Study of the rate of conversion of D-penicillamine to D-penicillamine disulfide in serum in vitro. (5) Study of the specificity (e.g., systemic lupus erythematosus, etc) of hypohistidinemia for rheumatoid arthritis. BIBLIOGRAPHIC REFERENCES: Gerber, D.A. Sulfhydryl-dependent thermal aggregation of human gamma globulin. Augmentation by hyaluronic acid. Arthritis and Rheumatism. 18:59-66, 1975. Gerber, D.A. Low free serum histidine concentration in rheumatoid arthritis. A measure of disease activity. Journal of Clinical Investigation 55:1164-1173. 1975.